Our Studies

RESEARCH TITLE

An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19

Short Title: Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC Study)

Purpose

In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral pneumonia cases of unknown cause. Coronavirus ribonucleic acid (RNA) was quickly identified in some of these patients. This novel coronavirus has been designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease caused by this virus has been designated coronavirus disease 2019 (COVID-19). There were 59 confirmed cases on January 5, 2020, 2,118 cases on January 26, 2020, rising to more than 20 million confirmed cases and 750,000 deaths as of August 16, 2020, according to various international health reporting agencies.

Hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from the plasma of individuals who recover and develop neutralizing antibodies, is a potentially useful therapeutic approach to COVID-19. Augmentation of the humoral immune (antibody) response using passive immunotherapy with hIVIG to SARS-CoV-2 at the onset of clinical progression before end-organ failure has developed may reduce the subsequent risk of further disease progression and death.

Study Objective

The primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient’s clinical status on Day 7. It includes seven mutually exclusive categories capturing the range of organ dysfunction that may be associated with the progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. The ordinal endpoint is defined as follows:

1. Death

2. End-organ failure

3. Life-threatening end-organ dysfunction

4. Serious end-organ dysfunction

5. Moderate end-organ dysfunction

6. Limiting symptoms due to COVID-19

7. No limiting symptoms due to COVID-19

Secondary endpoints include time to the three least favorable categories, time to the two most favorable categories, and the pulmonary only and thrombotic only components of the primary ordinal outcome. Mortality, adverse events (AEs), including infusion reactions, and biological correlates of therapeutic activity are also assessed. Because there is no established endpoint for evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant outcomes, including outcomes used in other COVID-19 treatment trials, will be recorded. Thus, the randomized groups (hIVIG + SOC versus placebo + SOC ) can be compared for multiple outcomes, and results can be compared or combined with other trials.

Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + SOC on the day of randomization (Day 0). Participants taking remdesivir prior to randomization may be enrolled if eligibility criteria are met. Randomized participants who were not taking remdesivir before randomization will start taking remdesivir immediately following the infusion of hIVIG or placebo unless remdesivir is contraindicated. Participants will be followed for 28 days and, if the trial goes to completion, the primary analysis will be completed after all participants are followed for 28 days.

 

Arm	Intervention/treatment
Experimental: Intervention Group Participants in this group will receive the investigational product and standard of care (SOC).	Drug: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion. Drug: Remdesivir Remdesivir will be given to participants in both groups as the standard of care (SOC).
Placebo Comparator: Control Group Participants in this group will receive a placebo and standard of care (SOC).	Other: Placebo Participants will receive a single infusion of the placebo (saline). Drug: Remdesivir Remdesivir will be given to participants in both groups as the standard of care (SOC).

 

Study Plan

Participants consent for the study and will be followed for 90 days.

 

Study Site

Sites	Hospital
Site 080 – 101	RSUP Dr. Cipto Mangunkusumo, Jakarta
Site 080 – 102	RSUD Dr. Soetomo, Surabaya
Site 080 – 103	RS Kabupaten Tangerang, Tangerang

  

Publication

“Hyperimmune immunoglobulin for hospitalized patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomized trial” was accepted by The Lancet, and published on January 27, 2022. Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00101-5/fulltext

RESEARCH TITLE

An International Observational Study of Outpatients with SARS-CoV-2 Infection

Short title: International SARS-CoV-2 Infection Observational Study (ICOS Study)

Purpose

SARS-CoV-2 is a coronavirus that emerged in China in late 2019, causing a novel Corona-Virus Induced Disease (COVID-19). COVID-19 is spreading rapidly throughout the world.  While a proportion of people with COVID-19 have sufficiently severe symptoms to require hospitalization at the time of initial symptom onset, the disease may remain mild in others. In some cases, there has been a worsening of symptoms a few days after initial presentation with relatively mild symptoms.  There is an urgent need to understand disease progression for individuals with SARS-CoV-2 infection/COVID-19 who do not require immediate hospitalization.

This study is an international, observational cohort study of adults with SARS-CoV-2 infection/COVID-19 managed as outpatients (not hospitalized).  This study will also be a platform for the enrolment of outpatients for randomized trials that the INSIGHT group will conduct.

Those with confirmed SARS-CoV-2 infection will form an observational cohort study and be followed for 28 days.  Procedures and data collection have been streamlined to facilitate the enrolment of a large number of adults at INSIGHT sites around the world.

The general aim of this study is to estimate the rate of disease progression for adults testing positive for SARS-CoV-2.  This study’s primary endpoint and the basis for sample size is hospitalization or death during the 28 day follow-up period.  Special facilities are being built/utilized for quarantine/public health reasons for those who are SARS-CoV-2 positive in some locations.  Hospitalization is defined as a stay for at least 18 hours, irrespective of the reason, at a hospital or one of these special facilities after study enrolment.

Secondary outcomes include participant-reported health status and change in the severity of dyspnoea.

As the understanding of the natural history of COVID-19 improves based on this and other studies, inclusion criteria and the data collection plan, including the outcomes assessed in this protocol, may be modified.

Study Objectives

The two primary objectives of this observational study are:

Among participants testing positive for SARS-CoV-2:

1. Estimate the rate of hospitalization or death during the 28 day follow-up period.
2. Identify risk factors for hospitalization or death.

Other objectives are:

1. Compare characteristics, including demographics, co-morbid conditions or immunosuppression, and other risk factors for disease progression, including hospitalization or death, for the global cohort and by geographic region between those who have a positive test for the SARS-CoV-2 virus versus those who have a negative test.
2. Among those positive for SARS-CoV-2:
   1. Evaluate health status and the percentage reporting excellent or very good health status during follow-up.
   2. Determine the percentage reporting a return to premorbid health status during follow-up.
   3. Evaluate change in the severity of dyspnoea using a standardized questionnaire during follow-up.
3. In a substudy involving selected sites, establish a repository of baseline upper respiratory and blood samples for future studies. These studies will be aimed at the molecular characterization of SARS-CoV-2 and the measurement of biomarkers that predict disease progression.  Among participants co-enrolling in INSIGHT 004: Genomics, DNA will be extracted for host genetics studies to investigate the pathophysiology and host-viral interactions of COVID-19.
4. Use the data collected to inform the design of future randomized intervention studies to reduce the rate of disease progression and morbidity.

Participant Selection

To be eligible for enrolment, participants must be ≥ 18 years of age, not be hospitalized (outpatients), and have signed informed consent.  Participants with SARS-CoV-2 infection will be followed for 28 days from enrolment.

Study Plan

Participants who consent for the study and have SARS-CoV-2 infection/COVID-19 will be followed for 28 days in an observational cohort study.

Procedures and data collection have been streamlined to facilitate the enrolment of a large number of adults at INSIGHT sites around the world.

The general aim of this study is to identify risk factors for disease progression, e.g., hospitalization or death.  This information will be used to plan and rapidly enroll randomized trials of treatments for COVID-19.  Protocols which are developed for the randomized trials by INSIGHT will be separate from this protocol.

Study Sites

Sites	Hospital
Site 612-801	Dr. Cipto Mangunkusumo Hospital, Jakarta
Site 612-802	Dr. Wahidin Sudirohusodo Hospital, Makassar

Study Updates

1^st enrollment was done on November 3, 2020, at Site 612-802, followed by Site 612-801 on November 6, 2020. Since then, the Site enrolls 8-10 subjects per week. On February 21, the enrolment rate at Site 612-801 started to decrease. Up to March 21, there had been 284 subjects enrolled from Indonesia, with 214 subjects already completed the Day 28 follow-up. The following is a summary of subjects screened and enrolled by sites:

Sites	Screened	Enrolled	Follow-Up	Completed Study
Site 612-801 – Cipto Hospital	180	179	164	128
Site 612-802 – Wahidin Hospital	105	105	100	86
Total	285	284	264	214

On January 21, Indonesia agrees to participate in sub-study specimen collection. The specimen collected will be used for future testing related to COVID-19 and research proposed by INSIGHT study team members. Approval has been granted from the Ethics Committee of NIHRD and the Faculty of Medicine, Universitas Indonesia, in March 2021. Sub-study is now ongoing at Site 612-802, but so far, no subject is recruited. Site 612-801 is still forming a team for the implementation of this sub-study.

RESEARCH TITLE

Dolutegravir and Darunavir Evaluation in adults Failing Therapy (D2EFT Study)

Background and Rationale

When this study was conceived, there was an urgent unmet need for a simple and cost-effective regimen of combination antiretroviral therapy (ART) for use in second-line therapy for the treatment of people with HIV-1 infection (HIV) in resource-limited settings. With a projected 30 million people around the world taking first-line therapy by 2020 and an anticipated failure rate of 15% per annum, the WHO recommended approach of switching to recycled nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in combination with a ritonavir-boosted protease inhibitor (standard of care, SOC) was neither simple nor sustainable.  The ideal combination second-line ART regimen in a resource-limited setting would satisfy 2 sets of criteria:

• primary criteria – include agents with:
  • high potency,
  • high genetic barriers to resistance
  • established safety profiles
  • good tolerance
• secondary criteria:
  • o able to be administered once-daily with no impact on the activities of daily living
  • o able to be co-formulated

Two major approaches to simplifying second-line ART regimens were identified for evaluation: first, simplified therapy with boosted protease inhibitor and an integrase inhibitor (derived from SECOND-LINE), and secondly dolutegravir with fixed nucleosides (tenofovir and lamivudine/emtricitabine, 3TC/FTC). This trial commenced with a comparison of the first simplification approach with SOC (stage 1) and expanded to allow comparison of both simplification approaches with each other and SOC (stage 2).

The SECOND-LINE study provided proof of principle that a regimen of combination antiretroviral therapy (ART) comprising raltegravir (integrase inhibitor) and lopinavir/r (a pharmaco-enhanced or ‘boosted’ protease inhibitor (b/PI)) provided non-inferior suppression of HIV replication over a 96-week period compared to applicable WHO-recommended therapy. In addition, evidence of better safety and tolerability was observed for the experimental regimen. This work was subsequently confirmed by others.

This study will build on that earlier work and examine the safety and efficacy of an innovative ART regimen as second-line therapy for HIV infection in low- and middle-income countries.

The experimental regimen in the SECOND-LINE study satisfied the primary criteria but not the necessary secondary criteria. The development of new drugs in the intervening period has allowed us to identify boosted darunavir (b/PI) and dolutegravir (DTG, an HIV integrase inhibitor) as an attractive combination satisfying all the selection criteria. Both drugs are licensed for the treatment of HIV infection.

Study Objective

General Aim

The primary objective is to compare the virological efficacy of the three regimens in the intention to treat (ITT) population. Virological efficacy is defined as the proportion of participants with plasma HIV RNA (pVL) <50 copies/mL at 48 weeks.

A number of secondary outcomes will be considered in order to compare the performance of the three regimens. Secondary analyses will focus on virological, immunological, safety, antiretroviral treatment change, medication adherence, quality of life, health care utilization, and costs of care.

Primary endpoint

The proportion of participants in each of the three arms whose pVL is <50 copies/mL at 48 weeks by intention to treat (ITT).

Secondary Endpoint

A number of secondary endpoints will be examined in this protocol by a randomized treatment arm. These will include, but not be limited to the following assessments at weeks 48 and 96:

Virological

• Proportion with pVL <200 copies/mL
• Proportion with pVL<50 copies/mL where those stopping randomized ART for any reason are classified as pVL>50 copies/mL (NC=F)

Immunological

• Mean change in CD4+ cell count from baseline

Metabolic

• Mean/median changes from baseline in fasted lipids (TC, LDL-c, HDL-c, and TG)

Safety

• A total number of participants with any serious adverse events (SAEs), adverse event(s) (AEs) grade 3 and above, and the cumulative incidence of SAEs and AEs ≥ grade 3.
• Total number of opportunistic diseases (AIDS events), deaths, and serious non-AIDS defining events and the cumulative incidence of these
• Adverse events associated with cessation of randomly assigned therapy
• Categorization of neuropsychological adverse events

Antiretroviral treatment

• Proportion who stopped randomized therapy by reason for stopping

Resistance

• Patterns of genotypic HIV resistance associated with virological failure

Adherence

• Adherence assessment and associations with virological outcomes

Quality of life

• Quality of life and anxiety and depression assessments

Health care utilization

• Health care utilization assessment

Costs of care

• Cost of care assessment

 

Study Sites

Sites	Hospital
Site 8881	Dr. Cipto Mangunkusumo Hospital, Jakarta
Site 8882	Dr. Soetomo Hospital, Surabaya
Site 8883	Dr. Wahidin Sudirohusodo Hospital, Makassar
Site 8884	Dr. Sardjito Hospital, Yogyakarta

  

Study Updates

week 48 primary analysis paper d2eft: The initial findings from these analyses were presented at an international meeting in late February 2023 and a publication will be submitted to a medical journal later this year.

RESEARCH TITLE

INA-RESPOND Observational Research on Infectious Disease Outbreaks and Difficult Cases of Unidentified Etiology in Indonesia (ORCHID Study)

Annex 1. In Response to SARS-CoV-2 Pandemic (ORCHID-COVID-19 Study)

Background:

Fifteen years after the Avian Influenza epidemic, Indonesia was recently hit by another respiratory outbreak, COVID-19, caused by the novel  SARS-CoV-2. This virus belongs to the Coronaviridae family, genus betacoronavirus, together with SARS-CoV and MERS-CoV. SARS-CoV-2 was first reported on 31 December 2020 in Wuhan, China, and then it rapidly spread globally to infect more than 10 million people in more than 200 countries by 15 July 2020. SARS-CoV-2 has infected more than 80,000 people in all provinces in Indonesia and has caused approximately 5% of death. In response to this pandemic, scientific research is necessary to systematically collect epidemiology, clinical data, and biological specimens. This study’s data are very important for identifying the best diagnostics, treatments, and prevention strategies to control the disease.

Objectives:

Primary Objective:

To identify COVID-19 and other respiratory infectious disease cases from hospitalized suspected COVID-19 patients.

Secondary Objectives:

• To describe the disease course and case management of COVID-19
• To assess the accuracy of diagnostic tests of COVID-19
• To better understand the pathogenesis of COVID-19
• To assess treatments and short-term outcomes of COVID-19
• To generate epidemiologic data to inform ongoing and future disease control and prevention efforts of COVID-19

Study Benefit (consistent with the main protocol)

• Provide a better understanding of COVID-19, its epidemiology, and clinical characteristics in Indonesia.
• Generate data to support evidence-based recommendations to health authorities for COVID-19 disease diagnostics, treatment, and prevention.
• Improve the INA-RESPOND Network’s capacity for conducting infectious disease research during dynamic outbreak scenarios, which will strengthen the specialization of the Reference Laboratory to identify SARS-CoV-2 and other respiratory pathogens.

Sample Size and Study Duration:

As a part of the ORCHID study that will enroll 4000 subjects over five years, this COVID-19 study will enroll 500 suspected COVID-19 subjects from 5 hospitals over one year.

Study Method:

This study will use the outbreak prospective observational arm of the study with an exploratory design. Therefore, no intervention will affect the standard of care or clinical outcome.

Study visit and Procedure:

Consistent with the main protocol, subjects will be seen during enrolment (visit 1), 7-14 days later (visit 2), and if necessary, one additional visit after visit two without a specific time frame. Data and specimens collected also refer to the main protocol.

• Inclusion criteria: Adult or child of any age undergoing a current episode of illness that is presumed COVID-19
• Exclusion criteria: none

Study Site

Sites	Hospital
Site 521	RS Universitas Udayana, Denpasar, Bali
Site 610	RSU Kabupaten Tangerang,Tangerang

 

Study updates

The data management team have completed the data au-dit for random sample subject in all sites. Meanwhile, the data audit for the critical data field on all subjects for site 521 is already done, while site 610 is still ongoing. All the study process close out at site RS Universitas Udayana has already finished since the site close-out visit (SCV) on 22 and 23 September 2022. The screenshot of the remote SCV is shown in Figure 1. The SCV of site RSU Kabupaten Tange-rang was arranged on 13 and 14 October 2022. The site is still preparing the pending/incomplete documents to be filed in the study’s regulatory binders before archiving. Figure 2 shows the study team at RSU Kabupaten Tangerang preparing for the SCV. We express our deepest gratitude for the efforts and good cooperation of the two sites during the research. We hope to continue to collaborate on INA-RESPOND research in the future.

Currently, the reference laboratory team is doing PCR SARS-CoV-2 test on all collected specimens (saliva, nasopharyngeal swab, oropharyngeal swab, urine, feces, and serum) from all COVID-19 cases. Some specimens that were positive SARS COV-2 at visit 1 (enrollment) will continue for another PCR SARS-CoV-2 testing on samples collect-ed at follow-up visit 2 (7- 14 days after enrollment). Meanwhile, the study team will determine the target pathogen to do molecular and serology testing for non-COVID-19 cases based on clinical symptoms.

Moreover, the study team is preparing two manuscripts (Overall study result and FLU PRO data), and it is discussing the tables and figures for the manuscript’s overall study results.

RESEARCH TITLE

Implementing a Combination of Clinical Parameters (Rapid Diagnostic Tests, Biomarkers and Standard of Care Procedures) for the Etiology Diagnosis of Pneumonia in Paediatric Patients to Improve Clinical Management in Indonesia (PEER-PePPes Study)

Study Overview:

Community-acquired pneumonia (CAP) requiring hospitalization contributes to the high morbidity and mortality among children under 5 years of age worldwide. In 2018, mortality rates among infant and toddler were 0,16% and 0,05%, respectively, in Indonesia. CAP can be caused by a variety of pathogens; viral, bacterial, and mixed. It is important to identify the causative pathogen because a comprehensive treatment that leads to the outcome is started with a precise diagnosis. An algorithm to differentiate viral, bacterial and mixed aetiologies of pediatric CAP based on clinical characteristics and biomarkers could improve empiric management of pediatric CAP in Indonesia. Studies on hospitalized CAP amongst pediatric patients in Indonesia have been limited, in part due to difficulty obtaining respiratory specimens and limited diagnostic capacity.

PEER-PePPeS study (Implementing a combination of rapid diagnostic tests, biomarkers, and standard of care procedures for the diagnosis of pneumonia in pediatric patients to improve clinical management in Indonesia study) is aiming to fill the gap in this research field in Indonesia. This study will evaluate the use of an algorithm utilizing several biomarkers and standard of care (SOC) procedures in differentiating these different pathogens in pediatric patients admitted to Tangerang, Semarang, and Yogyakarta hospitals in Indonesia. Secondary objectives of the study include (1) identifying the aetiologies of pneumonia in children in Indonesia; (2) documenting outcomes; (3) evaluating the use of each RDT (influenza, RSV, Pneumococcus), biomarkers (Haematology, CRP, PCT), and SOC (Chest X-Ray) in distinguishing viral and bacterial pathogens; and (4) providing updated strains of circulating viruses, bacteria, and antibiotic resistance.

The results of this study will impact case management in children with pneumonia, from an accurate diagnosis to appropriate treatment and development of prevention strategies. Subsequently, they should contribute significantly to the reduction of childhood morbidity and mortality in Indonesia. The proposed clinical pathway can inform management policies at the hospitals and highlight potential aetiologies and diagnostics that should be considered by clinicians, microbiologists, and clinical pathologists. This clinical pathway may also change the policies of the national insurance company by informing decisions on the diagnostic testing that is covered under the program currently and improving the cost-benefit ratio. Improved diagnostics and treatments can enable earlier commencement of appropriate treatment and decreased hospitalization time. The identification of influenza or other viruses as the causes of pneumonia can help to change the current perceptions of clinicians and health policymakers regarding the ability of these viruses to cause severe illness and improve the provision of antivirals. As the awareness will be enhanced and new policies may be applied, the private sector (e.g., pharmaceutical companies and diagnostic test manufacturers) may be motivated to improve the performance of their products regarding efficacy, sensitivity, and specificity.

The study may also have an impact on enhancing surveillance for pathogens, especially influenza H5N1, that may cause a pandemic threat.  Improved information regarding the pathogens causing pneumonia will help to identify and highlight research priorities in pediatric pneumonia and enable health programs to develop improved control and prevention measures at the community level.

Summary of Study Update: 

Screening and enrolment of subjects ended on September 30, 2019. Out of 564 patients, a total of 189 subjects were enrolled from four study sites: 74 subjects from Tangerang hospital, 47 subjects from Kariadi hospital including its satellite sites e.g. Tugurejo hospital and Bhakti Wira Tamtama hospital, 52 subjects from Sardjito hospital, and 16 subjects from An- Nisa hospital). The most common screen failure reasons were subjects were hospitalized more than 24 hours at enrollment, subjects had a condition that might interfere with study procedure and compliance (based on clinicians’ judgment), and subjects refuse to join the study. The major challenge that the study team encountered was determining the probable etiology. Distinguishing colonization from infection was also a major challenge when these organisms are detected in respiratory specimens. The detection of multiple potential pathogens in a single patient can also present a problem with assigning causality. Based on literature reviews, the PIs and study team members proposed nine rules of PEER, which can help determine the real pathogen from all viruses and bacteria detected using culture, molecular testing, and serology analysis. An algorithm based on laboratory markers is being developed to distinguish bacterial and viral infections in children with pneumonia.

Due to the current pandemic situation, our focus is temporarily shifted to support the Ministry of Health RI in controlling COVID-19 in Indonesia. Thus, the PEER-PePPes study has been extended to December 2020.

RESEARCH TITLE

A Prospetive Observational Cohort Study on HIV Infection and Risk Related Coinfections/Comorbidities in Indonesia

Rationale

Although national policies and collaborative actions have been placed to scale up HIV/AIDS treatment and prevention program, the HIV/AIDS epidemic in Indonesia is still increasing. The interaction of HIV/AIDS and coinfections/comorbidities complicate their clinical management and often associated with unfavorable health outcomes, mostly because of immunocompromised state or chronic inflammation, drug-drug interactions or toxicities or other immunologic reactions. There were limited data on virologic suppression in Indonesia and our laboratory capacity to assess HIV/AIDS virologic suppression were also limited. In addition, the existing information system on HIV/AIDS did not support data linkage across healthcare facilities in Indonesia. Nation-wide studies on HIV/AIDS and coinfections/comorbidities within various groups of patients are greatly needed to identify areas for improvement in HIV/AIDS clinical management and control program in Indonesia.

Objective

General aim

To collect standardized baseline and longitudinal data describing the course of HIV disease in antiretroviral-naive and treatment-experienced individuals to inform policy.

Primary objective:

To describe baseline socio-demographic and clinical characteristics, coinfections and comorbidities, treatment patterns and outcomes, and causes of mortality of people living with HIV/AIDS in Indonesia over 3 years.

Study Design

INA-PROACTIVE is a multicenter, prospective, observational cohort study of HIV positive antiretroviral-naïve and treatment-experienced individuals. No investigational treatment or intervention will be used by this study. All participants will be managed according to the Indonesian HIV/AIDS Treatment Guideline and the Standard of Care (SoC) in local clinical setting, with the addition of rapid HIV viral load, CD4 cell count and syphilis testing.

Data will be collected on all participants at baseline and follow up visits every 6 months (±3-month window period). Additional follow up data may be collected on selected participants who meet additional study follow up criteria.

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Progress and Updates

The INA104 (PROACTIVE) study site close-out activity was completed in October 2023, and research documents from the site have been archived with the INDOARSIP vendor. Con-currently, the data management team is undertaking general cleaning of data that has been entered, following thorough quality assurance checks across the site.

The first post-close-out activity involves preparing the final study report. This report, based on an interim report, serves as an attachment for site closure notification to both the central ethics com-mission (FK-UI RSCM Ethics Committee) and local ethics committees. Notifications, along with the interim report, are slated for submission in December 2023. Additionally, if necessary, these will also be sent to the site Director/Education and Research Department.

The second post-close-out activity focuses on writing a scoping review. This review aims to comprehensively understand HIV research conducted in various fields and identify gaps in HIV research in Indonesia. It encompasses a thorough examination of HIV research reports and outcomes in Indonesia, from the early stages of the epidemic to the present. The Secretariat team, along with Re-search Assistants, are currently preparing the protocol scoping review. Simultaneously, they have begun searching and reviewing literature on HIV research in Indonesia using two journal databases:Pubmed and Garuda (Garba Rujukan Digital /Digital Referral Platform: https://garuda.kemdikbud.go.id/).

The third post-close-out activity is the preparation of manuscripts. The secretariat, study core team, and NIAID team, in collaboration with the PI and Co-PI from each site, are developing three main manuscripts. The first manuscript, focusing on baseline characteristics and predictors of mortality within one year (‘Baseline Characteristics and One-Year Mortality’), is in circulation among all teams and is targeted for publication in the Journal of the International AIDS Society.

The other two manuscripts are in the developmental phase. These include an initial analysis of mortality within three years (‘Early Analysis of Three-Years Mortality in People Living with HIV’) and a study on virological, immunological, disease, and clinical progression (‘Clinical, Immunological, and Virological Responses of HIV-infected People with AntiRetroviral Therapy in a Nationwide Indonesian Cohort’). Current efforts include determining the writing team and assigning specific responsibilities for the writing process. The composition of the writing teams for each manuscript is being decided based on the initial concept plans and the enthusiasm shown by the study sites.

Table 1. Ethic Committee List

RESEARCH TITLE

An Observational Study of the Causes, Management, and Outcomes of Community-acquired Sepsis and Severe Sepsis in Southeast Asia

Bacterial and viral infectious diseases are still the leading cause of death in Southeast Asia, comparable to injuries, cardiovascular diseases and other non-communicable diseases. Sepsis is defined as the body’s response to infectious diseases, including bacterial and viral causes. Sepsis should be considered as a medical emergency just like a heart attack or stroke because there is an interruption in the supply of oxygen and nutrients to the tissues, and emergency treatment is required. The definition of sepsis is broader than febrile illness as patients with severe infectious diseases may not present with fever, and infectious causes may be overlooked by physicians. On the other hand, it is not uncommon for patients who are diagnosed with sepsis on admission to later have a confirmed non-infectious diagnosis.

Recognition of sepsis as a specific syndrome is the most important key for improvements in diagnostic and treatment strategies for infectious diseases. The 1992 statement from ACCP/SCCM (American College of Chest Physicians and the Society of Critical Care Medicine) Conference introduced a definition of “systemic inflammatory response syndrome (SIRS)”. SIRS was considered when patients have more than one of the following clinical findings:

• Body temperature higher than 38oC or lower than 36oC
• Heart rate higher than 90/min
• Hyperventilation evidenced by respiratory rate higher than 20/min or PaCO2 lower than 32 mmHg
• White blood cell count higher than 12,000 cells/uL or lower than 4,000/uL

The European Society of Intensive Care Medicine (ESICM)/SCCM found a problem that 71% of clinicians and researchers cited no common definition of sepsis. In 2001, the criteria of SIRS were revised so that the updated criteria are useful to both clinicians caring for patients at bedside and to researchers designing observational studies. The revised criteria by SCCM/ESICM/ACCP/ATS/SIS were also to respond the sepsis research agenda to include the “standardization of research protocols”. The improvement was focused on an increase in sensitivity to identify most patients with infection, while minimally sacrifice inevitable specificity. The 2003 statement from SCCM/ESICM/ACCP/ATS/SIS Conference introduced the updated definition of sepsis and SIRS (Scheme 1). The use of this definition has been continuously recommended in 2004, 2008 and 2012 surviving sepsis campaign.

A recent study also confirmed that the 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definitions have higher sensitivity to include patients with clinically or microbiology proven infections compared to the 1992 ACCP/SCCM sepsis definition. Of 827 patients admitted to the ICU within a one year period, Weiss et al found that 16 of 282 patients with clinically or microbiologically proven infections did not meet the 1992 ACCP/SCCM sepsis definition, but all 282 patients with clinically or microbiologically proven infections met the 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition. The 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition also has a higher sensitivity to predict death. Therefore, we aim to use the current 2003 SCCM/ESICM/ACCP/ATS/SIS sepsis definition for inclusion criteria of sepsis patients (Scheme 1) in this sepsis study.

In addition, the recognition of sepsis cannot replace the diagnosis and management of specific clinical syndromes, such as acute diarrhea or acute encephalitis. However, in those patients, sepsis should be considered as an add-on to the diagnosis, and management of sepsis, in general, should not be overlooked. The recent Fluid Expansion as Supportive Therapy (FEAST) study highlights the need for a much greater understanding of this syndrome, its causes and management strategies in resource-limited settings.

Although infectious diseases are major causes of death in Southeast Asia, the epidemiology of its causes is poorly understood. This is largely because a number of tropical infectious diseases cannot be diagnosed by standard microbiology facilities. For example, most viral infections require specific PCR assays, and rickettsial diseases require an extra blood sample on admission and on convalescent phase for definite diagnosis. Understanding the epidemiology of the causes of sepsis is the corner stone to improve guidelines for diagnosis and management of sepsis specific to the area.

The Management of Severe sepsis in Asia’s Intensive Care units (MOSAIC) conducted a multicenter cohort study involving 16 countries in Asia. In 2009, results of this study were reported and indicated an overall hospital mortality rate from all causes of sepsis to be 44.5%. Similarly, a 2-year epidemiological sepsis study conducted at the Prince Songkla University Hospital in Thailand showed that the hospital and ICU mortality rate of severe sepsis and septic shock was 49.7% and 39.2% respectively and that an estimated 40.5% of the total ICU mortality cases of sepsis were felt to be caused by community-acquired disease. A retrospective review of data from 10 provincial hospitals in Northern Thailand compared to the national death registry between 2004 and 2010 revealed an incidence of community-acquired bacteremia (CAB) increasing from 16.7 to 38.1 per 100,000 people per year. Over that same time period the mortality rate associated with CAB increased from 6.9 to 13.7 per 100,000 people per year. Overall, of those patients admitted to the hospitals with CAB 37.5% died within 30 days of admission. These 3 studies serve to confirm the magnitude of the problem in Southeast Asia and the need to collect more empirical data. A review of the literature also confirms that there are very few population-based studies evaluating the incidence, causes and trends in CAB in low- and middle-income countries, an important omission since such information is required for strategic planning of available healthcare resources, together with disease prevention programs.

Current evidence suggests that a wide range of pathogens is responsible for sepsis and severe sepsis in Southeast Asia. An observational study conducted by Suttinont et al in 845 patients in 2006 showed that major causes of acute undifferentiated fever in Thai agricultural workers are leptospirosis (37%), scrub typhus (20%), influenza (11%), murine typhus (2.8%) or other bacterial infection (1.2%). Leptospirosis has also been reported as the major cause of fever in 13/137 in adults in Indonesia. Acute rickettsial infection was also identified as the cause of fever in 115/427 (27%) adults with negative blood cultures admitted to Mahosot Hospital in Vientiane, Laos, and in 9/137 in adults with acute undifferentiated fever in Semarang, Indonesia. Gram-negative aerobes accounted for 90% of causes of sepsis (67% Salmonella typhi, 10% Escherichia coli, 5% Klebsiella spp. and 3% Salmonella para-typhi B) in adults and children admitted to infectious disease hospitals in southern Vietnam. That study highlighted that over 70% of the Salmonella typhi isolated were multi-drug-resistant. Similarly, Salmonella enterica serotype Typhi predominates as the cause of bacteremia in Cambodia, while Burkholderia pseudomallei is a major cause of bacteremia in Thailand. However, estimates vary on the incidence of community-acquired sepsis caused by Burkholderia pseudomallei. A study in Southern Thailand of community-acquired severe sepsis caused by Burkholderia pseudomallei indicated a 3.8% incidence. A recent retrospective review of CAB cases in Northern Thailand between 2004 and 2010 indicated that Burkholderia pseudomallei was the sepsis causative agent in 20.2% of adults, 14.3% of children aged 1-15 years and 1.6% in infants less than one year of age.

In an 8-year-long review of blood culture isolates from patients presenting to the Emergency Department of the Hospital Universiti Sains Malaysia beginning from 2002, 55.2% were found to be caused by gram-negative aerobes. Of these, increased drug resistance was noted with less than 80% sensitivity to ampicillin, cotrimoxazole and ciprofloxacin. Other studies highlight that often the cause of sepsis is unknown and a retrospective review of community-acquired bacteremia studies between 1990 and 2010 in South and South-east Asia identified that pathogenic organisms were only isolated in 12% of adults and 7% of children. The paper argues that better detection would lead to better patient outcomes and improved patient management. Goal-directed therapy and appropriate administration of antibiotics within 6 hours was noted to improve outcomes in sepsis patients at Siriraj Hospital in Bangkok, Thailand.

The first aim of this proposal, therefore, is to determine the causes of severe acute infectious illnesses (presenting with sepsis and requiring hospitalization by attending physicians) at multiple study sites across Southeast Asia. This study will also establish a regional repository of samples with robust clinical data to facilitate future pathogen discovery programs and allow future development and assessment of novel diagnostic tests. As stated above, the causes and incidence of community-acquired sepsis and severe sepsis vary. Treatment is initiated based on a presumptive diagnosis taking into account the clinical presentation, initial laboratory data as well as the local guidelines for the management of sepsis and severe sepsis. In many cases a definitive confirmation of the causative agent is not known until much later if at all. While guidelines are available that provide guidance for the treatment of the common causes of sepsis, some causes require a different choice of antibiotics and anti-viral agents. For example:

• Burkholderia pseudomallei is intrinsically resistant to commonly used first-line antibiotics which are used to treat sepsis in Southeast Asia including penicillin, aminoglycosides and most cephalosporins. Regimens including ceftazidime or a beta-lactam antibiotic such as one of the carbapenems are also indicated.
• Listeria monocytogenes possesses a natural in-vitro resistance to older quinolones, fosfomycin, and expanded-spectrum cephalosporins. Treatment is typically based on a synergistic association of high doses of aminopenicillin (ampicillin or amoxicillin) and gentamicin. Although rifampin, vancomycin, linezolid, and carbapenems have been proposed as possible alternatives, trimethoprim is generally used in case of intolerance to beta-lactams.
• Sepsis caused by the Rickettsiae group of organisms is best treated by early initiation of specific antibiotics including doxycycline, chloramphenicol or a fluoroquinolone.
• Sepsis and encephalitis caused by Herpes simplex would warrant treatment with intravenous acyclovir.

When considering the prevalence of the different causes of sepsis that this study is likely to encounter at the study sites it is important to consider a sample size that will detect those causes that would lead to a different choice of antibiotics or anti-virals compared to standard therapy. An informal review of hospital records in Ho Chi Minh City in 2012 revealed that the prevalence of Listeria monocytogenes, Burkholderia pseudomallei, Herpes simplex and Rickettsiae organisms as the confirmed cause of community-acquired sepsis and severe sepsis was greater than 2% but less than 5%. Similarly, the recent retrospective study of CAB in Northern Thailand showed that if a 5% prevalence of the difference causes of disease was assumed then this would miss important causes including Burkholderia pseudomallei and Haemophilus influenzae in infants under one year of age (2% and 2.8% prevalence respectively), Streptococcus pneumonia in adults (2.5% prevalence), Group A Streptococcus in all age groups (2.2-3%), and extended spectrum beta lactamase (ESBL) Escherichia coli in adults (2.9% prevalence). These data suggest that a study powered to detect 5% prevalence of any particular cause would likely miss some important causes resulting in cause-appropriate treatment not being administered. This has obvious implications for patient survival, particularly when mortality rates are known to be high if appropriate treatment is not administered quickly. These data would also indicate that detecting a 2% prevalence of the different causes of sepsis would be more clinically appropriate and likely lead to higher survival rates for patients in this study.

Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Around 20-40% of sepsis patients presenting to the hospitals develop severe sepsis, which is associated with a very high mortality rate. Apart from antibiotic and anti-viral treatment being an important component of sepsis survival, the overall comprehensive clinical management of the patient is critical, particularly for those who develop severe sepsis. In 2004, an international group of experts in the diagnosis and management of infectious diseases published the first internationally accepted guidelines that the bedside clinician could use to improve outcomes in severe sepsis (sepsis plus any acute organ dysfunction). This “surviving sepsis campaign (updated in 2008)” aims to increase awareness and improve the acute management in severe sepsis. Acute management of severe sepsis during the first 48 hours is very important to reduce mortality. The MOSAIC’s multinational cohort study reported that the overall compliance with the Surviving Sepsis Campaign’s resuscitation and management bundles for severe sepsis in adult patients in Asian countries was only 7.6% and 3.5% respectively. These numbers are much lower than those reported by other similar studies in Europe and the Americas.

Nonetheless, most of the interventions in the “surviving sepsis campaign” are based on facilities available in the developed world. It is very likely that management of sepsis and severe sepsis varies widely across Southeast Asia, in part due to limited resources.

The second aim of this proposal, therefore, is to observe current acute management (within the first 48 hours) of patients presenting with sepsis and severe sepsis to design practical interventions that could reduce the mortality in the future. This study will observe the routine practice in detection of severe sepsis among sepsis patients, and the overall management of patients with sepsis and severe sepsis at multiple study sites across Southeast Asia. This study will focus on observations of early and basic management, including fluid management, blood pressure control, timely administration of antibiotics, and source control, which is likely to be the most cost-effective intervention even in resource-constrained settings.

Outcome from patients presenting with sepsis and severe sepsis is dependent on many factors, including causes of infection, severity of infection, sepsis resuscitation, antimicrobial treatment and host genetic factors. There is a lack of studies showing genetic factors associated with outcomes in patients with sepsis and severe sepsis in developing countries. A recent retrospective study in 669 Thai patients with culture-proven melioidosis admitted to Sappasithiprasong Hospital shows that hypofunctional genetic variant TLR51174C>T is associated with reduced organ failure and improved survival in melioidosis. Understanding all predictive factors associated with inflammatory responses, organ failure, and mortality of patients with sepsis and severe sepsis, including genetic factors, would be very important to improve the management and outcome of this group of patients in the future. Therefore in this study we will ask adult subjects if they wish to provide one additional sample of blood to be stored for later genetic testing. This is optional and subjects can chose to not consent to providing this additional sample without affecting their eligibility to be part of the sepsis study.

RESEARCH TITLE

Tuberculosis Research of INA-RESPOND on Drug Resistance (TRIPOD)

Tuberculosis (TB) continues to be a health problem in the world, especially in developing countries and despite the use of anti-TB treatments and BCG vaccination TB incidence continues to rise and is a re-emerging disease that was declared a global health emergency by the World Health Organization (WHO) in 1995. In 2008, WHO estimated that there were 9.2 million new TB patients and 4.1 million of whom were patients with Acid-Fast Bacillus (AFB) positive with a mortality rate of 1.7 million patients per year throughout the world.

Based on the WHO Report 2013, Indonesia ranked third in the world with an estimated prevalence in 2012 is 730,000 cases and TB incidence is 460,000 cases with mortality number 67,000.³ This condition is exacerbated by the increasing incidence of TB/HIV comorbidity and the growing number of cases with TB Multidrug Resistance TB (MDR) or even Extensively or Extremely Drug Resistance (XDR). This situation will lead to an epidemic of TB that is difficult to manage and continues to be a major public health problem. Previous drug resistance TB surveys around Indonesia revealed that in Timika district at Papua 2004, 2% of new TB cases are MDR TB cases, in Central Java province 2006, 1.8% of new TB cases and 17.1% of retreatment TB cases are MDR TB cases. Survey in Makassar 2007 revealed higher number that 4.1% of new TB cases and 19.2% of retreatment TB cases are MDR TB cases. WHO Report 2013 estimation in 2012 for Indonesia gave a lower number which are 1.9% of new TB cases and 12% of retreatment TB cases are MDR TB cases.

The Indonesia Health Profile study reported 194,000 new TB cases in 2011 based on positive smear results. TB control efforts were implemented in Indonesia starting in 1969, Directly Observed Treatment Shortcourse chemotherapy (DOTS) began in 1995. Nevertheless these efforts to date have not eliminated the TB burden.

Treatment success is known to be associated with several factors. These include patient related factors, such as host response, age, gender,smoking habit,nutritional status, comorbidities (diabetes and HIV). Mtb characteristics are also associated with outcome, including number of bacteria and Mtb strain (e.g Beijing strain). Pharmacokinetics and pharmacogenomics, particularly with infections with drug-resistant strains are additionally associated with outcome.

Data on the prevalence of MDR-TB or XDR-TB among naïve or retreatment TB cases is limited to several centers in Indonesia.  This study will be the first to follow up new and previously treated TB patients in hospitals in Indonesia. Prevalence data for drug-susceptible and MDR TB, along with corresponding treatment outcomes, will be beneficial to inform national TB programs.  Additionally, data collected from this study will be useful for planning future research studies in Indonesia  evaluating novel diagnostics, markers of response to treatment and new therapies.

RESEARCH TITLE

The Etiology of Acute Febrile Illness Requiring Hospitalization (AFIRE)

Febrile illnesses account for approximately 20-25% of hospitalizations in Indonesia and present a major cause of morbidity and mortality. Fever can be attributed to noninfectious causes. However, in developing countries, a clinical presentation with fever is usually linked to an infectious etiology. Though several studies have been implemented to study specific infectious disease agents such as dengue, diarrhea, or influenza-like illness, large-scale studies to identify causes of febrile illnesses in Indonesia have not been conducted. Further, there is a reasonable percentage of patients for whom the cause of the infectious etiology is unknown. To identify the etiology of infectious diseases, microscopic examinations, bacterial and viral cultures, molecular, antigen or antibody assays are needed. Clinicians often make the diagnoses solely on the clinical presentation as laboratory diagnostic capacities are lacking, high costs involved in specialized diagnostic testing, or the inability of a majority of patients to afford to test. This can lead to inappropriate clinical management and inappropriate use of expensive antibiotics, which may contribute to increasing drug resistance.

Several studies have been conducted to evaluate febrile illness in various contexts in Indonesia. These studies have identified pathogens in specimens collected from several acute undifferentiated fever studies. One of the first reports was from Jakarta (Anderson et al.) based on the collection of specimens from hospitalized patients with an unapparent febrile illness in 1971-72. Salmonella and arbovirus infections were the major etiologies identified whereas leptospira, rickettsia, brucella, and toxoplasma infections were serologically identified in a few patients. Another study during this decade was conducted in Klaten, Central Java in 1978 (Olson et al.) and identified alphavirus and flavivirus as the etiologies of fever. In 1995, Suharti et al. found that dengue comprised only 49% of total clinically suspected dengue cases in Semarang, Central Java. Other etiologies included rickettsia, hantavirus, leptospira, rubella, chikungunya, and influenza. In 2002-2003, Vollaard et al identified the high prevalence of salmonella typhi and parathyphi infections (9% and 3%, respectively) as confirmed by bacterial culture, in ambulatory and hospitalized febrile patients in Jakarta.

In 2005-2006, Gasem et al. emphasized the importance of considering leptospira and rickettsia infections in patients with acute undifferentiated fever in primary health centers and hospitals in Semarang. During the same period, Suwandono et al published findings suggesting that dengue should be monitored carefully, as it contributed 15% of acute febrile illness in patients who visited the primary care facilities in Jakarta. Chikungunya shared a similar prevalence, but there was no evidence of endemicity. An observational study from 2000-2008 among adults in Bandung by Alisjahbana et al showed similar etiologies of fever among ambulatory and hospitalized patients. In their study the proportion of cases attributable to the different etiologies were: dengue 12%, influenza 10%, chikungunya 8%, and typhoid 2.4%. Unlike in Jakarta, chikungunya cases in Bandung were found all year round. These studies and national influenza surveillance also detected novel and/or emerging infectious agents such as zika virus in Klaten, hantavirus in Semarang and Bandung, and influenza H5N1 subtype in many areas.

As the studies were designed to test for specific agents, a large proportion of cases remained unidentified. The most frequent etiologies from these studies were also the important agents found in Thailand, Myanmar, Thailand border, and Malaysia (Ellis et al., Leelarasamee et al, Brown et al.).

However, these above-mentioned studies though useful were limited in their scope to particular regions or etiologies and did not collect clinical data, outcomes, and etiologies to measure disease burden systematically.

This protocol is designed to provide data that represents the epidemiologic profile of infectious diseases in several large hospitals, by conducting a study to record epidemiological data and identify the etiologies of fever. It will attempt to do so by including hospitals and clinical centers in different parts of the country and collaboration with physicians and researchers across Indonesia.

It is hoped that this will lead to recommendations that will impact clinical care and management of patients which could include changes in the diagnostic testing profile currently available as standard of care (SoC) for patients with febrile illnesses. It will also enable the implementation of an effective clinical research network for the study of infectious diseases in Indonesia.